Faculty Bibliography

OBJECTIVE:To demonstrate incidental findings and scoliosis on whole-body MRI (WBMRI) in patients with neurofibromatosis type 1 and 2 (NF1 & NF2, respectively), and schwannomatosis. MATERIALS AND METHODS/METHODS:Institutional review board approval and written informed consent were obtained for this prospective HIPAA-compliant study. A total of 247 subjects (141 with NF1, 55 with NF2, 51 with schwannomatosis; 132 women (53.5%); mean age, 41 years, range, 18-97 years) underwent WBMRI using coronal STIR (TR/TE: 4190/111 ms, TI: 150 ms) and T1-weighted images (TR/TE: 454/10 ms), 10-mm slice thickness, imaging time ~40 min. Images were reviewed for the presence of incidental findings, outside of nerve sheath tumors. The presence of scoliosis was recorded and curve morphology was assessed and quantified. RESULTS:Incidental findings other than scoliosis were recorded in 104/247 (42%) patients, most often affecting the musculoskeletal system (65/247 patients, 26%). We found 16/247 (6.5%) significant incidental findings likely to affect clinical management, including avascular necrosis of bone in eight patients (five with NF2), eight insufficiency fractures, and four non-neurogenic neoplasms (Hodgkin's lymphoma, liposarcoma, dermoid cyst, large uterine myoma requiring excision). Scoliosis was seen in 50/247 patients (20%), including 8/55 with NF2 (15%) and 11/51 with schwannomatosis (22%). CONCLUSIONS:Incidental findings in the neurofibromatoses frequently involve the skeleton. Given the relatively high incidence of unsuspected osteonecrosis and stress fractures, close attention to the skeleton on WBMRI is advised. In addition, knowledge of common incidental findings can help clinicians prepare patients who undergo WBMRI for potential unexpected findings.

OBJECTIVE:To describe the involvement of lower leg muscles in boys with Duchenne muscular dystrophy (DMD) by using MR imaging (MRI) and spectroscopy (MRS) correlated to indices of functional status. SUBJECTS AND METHODS/METHODS:Nine boys with DMD (mean age, 11 years) and eight healthy age- and BMI-matched boys (mean age, 13 years) prospectively underwent lower leg MRI, 1H-MRS of tibialis anterior (TA) and soleus (SOL) for lipid fraction measures, and 31P-MRS for pH and high-energy phosphate measures. DMD subjects were evaluated using the Vignos lower extremity functional rating, and tests including 6 min walk test (6MWT) and 10 m walk. RESULTS:DMD subjects had highest fatty infiltration scores in peroneal muscles, followed by medial gastrocnemius and soleus. Compared to controls, DMD boys showed higher intramuscular fat (P = 0.04), lipid fractions of TA and SOL (P = 0.02 and 0.003, respectively), pH of anterior compartment (P = 0.0003), and lower phosphocreatine/inorganic phosphorus ratio of posterior compartment (P = 0.02). The Vignos rating correlated with TA (r = 0.79, P = 0.01) and SOL (r = 0.71, P = 0.03) lipid fractions. The 6MWT correlated with fatty infiltration scores of SOL (r = -0.76, P = 0.046), medial (r = -0.80, P = 0.03) and lateral (r = -0.84, P = 0.02) gastrocnemius, intramuscular fat (r = -0.80, P = 0.03), and SOL lipid fraction (r = -0.89, P = 0.007). Time to walk 10 m correlated with anterior compartment pH (r = 0.78, P = 0.04). CONCLUSION/CONCLUSIONS:Lower leg muscles of boys with DMD show a distinct involvement pattern and increased adiposity that correlates with functional status. Lower leg MRI and 1H-MRS studies may help to noninvasively demonstrate the severity of muscle involvement.

CONTEXT/BACKGROUND:Recent studies have suggested that obesity in men is associated with increased fracture risk. Obesity in men is also associated with dysregulation of the GH/IGF-I and gonadal steroid axes, important regulators of bone homeostasis. OBJECTIVE:The aim of the study was to investigate body composition and endocrine determinants of bone microarchitecture and mechanical properties in obese men. DESIGN AND SETTING/METHODS:We conducted a cross-sectional study at a clinical research center. PARTICIPANTS/METHODS:Thirty-five obese men (mean age, 33.8 ± 6.4 yr; mean body mass index, 36.5 ± 5.8 kg/m(2)) participated in the study. OUTCOME MEASURES/METHODS:Distal radius microarchitecture and mechanical properties were measured by three-dimensional high-resolution peripheral quantitative computed tomography and microfinite element analysis; body composition by computed tomography; bone marrow fat by proton magnetic resonance spectroscopy; total and free estradiol and testosterone; IGF-I; peak glucagon-stimulated GH; 25-hydroxyvitamin D. RESULTS:Men with high visceral adipose tissue (VAT) had impaired mechanical properties compared to men with low VAT (P < 0.05), despite comparable body mass index. VAT was inversely associated and thigh muscle was positively associated with mechanical properties (P < 0.05). Bone marrow fat was inversely associated with cortical parameters (P ≤ 0.02). Free estradiol was positively associated with total density (P = 0.05). Free testosterone was positively associated with trabecular thickness and inversely with trabecular number (P ≤ 0.05). Peak stimulated GH was positively associated with trabecular thickness, as was IGF-I with cortical area (P ≤ 0.04). CONCLUSION/CONCLUSIONS:VAT and bone marrow fat are negative predictors and muscle mass is a positive predictor of microarchitecture and mechanical properties in obese men. Testosterone, estradiol, and GH are positive determinants of trabecular microarchitecture, and IGF-I is a positive determinant of cortical microarchitecture. This supports the notion that VAT is detrimental to bone and that decreased GH and testosterone, characteristic of male obesity, may exert deleterious effects on microarchitecture, whereas higher estradiol may be protective.

Women with anorexia nervosa (AN) have elevated marrow fat mass despite low visceral and subcutaneous fat depots, which is inversely associated with bone mineral density (BMD). Whether marrow fat mass remains persistently elevated or decreases with recovery from AN is currently unknown. In this study, we investigated changes in marrow fat in women who have recovered from AN (AN-R). We also studied the relationship between preadipocyte factor (Pref)-1-a member of the EGF-like family of proteins and regulator of adipocyte and osteoblast differentiation-and fat depots and BMD in AN-R compared with women with AN and healthy controls (HC). We studied 29 women: 14 with active or recovered AN (30.7 + 2.2 years [mean ± SEM]) and 15 normal-weight controls (27.8 ± 1.2 years). We measured marrow adipose tissue (MAT) of the L4 vertebra and femur by (1) H-magnetic resonance spectroscopy; BMD of the spine, hip, and total body by DXA; and serum Pref-1 and leptin levels. We found that MAT of the L4 vertebra was significantly lower in AN-R compared with AN (p = 0.03) and was comparable to levels in HC. Pref-1 levels were also significantly lower in AN-R compared with AN (p = 0.02) and comparable to levels in healthy controls. Although Pref-1 was positively associated with MAT of the L4 vertebra in AN (R = 0.94; p = 0.002), we found that it was inversely associated with MAT of the L4 vertebra in HC (R = -0.71; p = 0.004). Therefore, we have shown that MAT and Pref-1 levels decrease with recovery from AN. Our data suggest that Pref-1 may have differential effects in states of nutritional deprivation compared with nutritional sufficiency.

OBJECTIVE:Abdominal adiposity is associated with increased cardiovascular risk and decreased GH secretion. The objective of our study was to determine the effects of GH on body composition and cardiovascular risk markers in abdominally obese women. MATERIALS AND METHODS/METHODS:In this randomized, double-blind, placebo-controlled study, 79 obese premenopausal women received GH vs placebo for 6 months. Primary endpoints were i) total abdominal (total abdominal adipose tissue, TAT) fat by computed tomography (CT) (body composition) and ii) high-sensitivity C-reactive protein (hsCRP) (cardiovascular risk marker). Body composition was assessed by CT, dual-energy X-ray absorptiometry, and proton MR spectroscopy. Serum cardiovascular risk markers, carotid intima-media thickness, and endothelial function were measured. RESULTS:Mean 6-month GH dose was 1.7±0.1 mg/day, resulting in a mean IGF1 SDS increase from -1.7±0.08 to -0.1±0.3 in the GH group. GH administration decreased TAT and hsCRP compared with placebo. In addition, it increased thigh muscle mass and lean body mass and decreased subcutaneous abdominal and trunk fat, tissue plasminogen activator, apoB, and apoB/low-density lipoprotein compared with placebo. Visceral adipose tissue (VAT) decreased and intramyocellular lipid increased within the GH group. Six-month change in IGF1 levels was negatively associated with 6-month decrease in TAT and VAT. One subject had a 2 h glucose >200 mg/ml at 3 months; four subjects, three of whom were randomized to GH, had 2 h glucose levels >200 mg/ml at the end of the study. CONCLUSION/CONCLUSIONS:GH administration in abdominally obese premenopausal women exerts beneficial effects on body composition and cardiovascular risk markers but is associated with a decrease in glucose tolerance in a minority of women.

CONTEXT/BACKGROUND:Anorexia nervosa (AN) is associated with depletion of body fat, loss of bone mineral density (BMD), and impaired thermogenesis. Brown adipose tissue (BAT) is lower in obese individuals and decreases during aging. Recent studies have suggested a link between BAT and bone metabolism. OBJECTIVE:Our objective was to investigate the presence and quantity of BAT in patients with AN, recovered AN (AN-R), and normal-weight controls and to study the relationship between BAT and BMD and body composition and investigate hormonal predictors of BAT. DESIGN AND SETTING/METHODS:This was a cross-sectional study at a clinical research center. PATIENTS/METHODS:Patients included 15 women: five with AN (mean age 30 ± 6.3 yr), five AN-R, and five healthy nonobese controls of comparable age. MAIN OUTCOME MEASURES/METHODS:Cold-activated BAT was determined by fluorodeoxyglucose-positron emission tomography/computed tomography. BMD of total-body, spine, and hip, fat and lean mass was determined by dual-energy x-ray absorptiometry. Single-slice magnetic resonance imaging at L4 was done for abdominal fat compartments, and preadipocyte factor-1 (Pref-1), T₃, and T₄ were measured. RESULTS:Within the AN group, one of five; in the AN-R group, two of five; and in the healthy nonobese control group, four of five subjects were BAT positive. Subjects were divided into groups based on the presence (n = 7) or absence (n = 8) of BAT. Both groups were of comparable age and body mass index. Women with BAT had higher total-body BMD, higher T₃, and lower Pref-1 compared with women without BAT. There was a positive correlation between BAT and BMD that remained significant after controlling for disease status and body mass index. CONCLUSION/CONCLUSIONS:Young women with AN have low cold-activated BAT, which may be due to impaired BAT thermogenesis. Young women with BAT have higher BMD and lower Pref-1 compared with women without BAT, suggesting that BAT may be involved in the regulation of stem cell differentiation into the bone lineage at the expense of adipogenesis.

CONTEXT/BACKGROUND:The pathogenesis and function of dorsocervical sc adipose tissue (DSAT) accumulation in HIV-infected patients is not known. Previous investigations using either UCP-1 expression or positron emission tomography have been inconclusive as to whether this depot represents brown adipose tissue (BAT). We investigated DSAT gene expression, including DIO2, a deiodinase that contributes to increased thermogenesis in brown fat, and simultaneously determined [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) uptake in lipodystrophic HIV and healthy control subjects. DESIGN/METHODS:Thirteen HIV-infected and three non-HIV-infected men were recruited. HIV-infected subjects had evidence of significant lipodystrophy, including fat atrophy of the face, arms, and legs, and/or fat accumulation of the neck and abdomen. Subjects were cooled, followed by [¹⁸F]FDG positron emission tomography/computed tomography, fat biopsy of DSAT, and measurement of resting energy expenditure (REE). HIV-infected subjects were characterized as lipohypertrophic and lipoatrophic and compared. RESULTS:Mean standardized uptake value of [¹⁸F]FDG and UCP-1 expression were not significantly different in DSAT among the groups. However, lipohypertrophic subjects demonstrated increased expression of DIO2 in DSAT compared with lipoatrophic subjects (P = 0.03). Among HIV-infected patients, DIO2 expression was strongly related to REE (r = 0.78, P = 0.002) and was a predictor of REE in multivariate modeling controlling for age, TSH, and lean body mass (r² = 0.79, P = 0.008). One control subject demonstrated typical BAT in the supraclavicular area. CONCLUSIONS:Adipose tissue accumulating in the dorsocervical area in HIV lipodystrophy does not appear to be classical BAT. However, DIO2 expression is increased in DSAT among patients with HIV lipodystrophy, particularly those with increased visceral adiposity, and is positively associated with energy expenditure.

PURPOSE: Patients with neurofibromatosis 1 (NF1), NF2, and schwannomatosis are at risk for multiple nerve sheath tumors and premature mortality. Traditional magnetic resonance imaging (MRI) has limited ability to assess disease burden accurately. The aim of this study was to establish an international cohort of patients with quantified whole-body internal tumor burden and to correlate tumor burden with clinical features of disease. METHODS: We determined the number, volume, and distribution of internal nerve sheath tumors in patients using whole-body MRI (WBMRI) and three-dimensional computerized volumetry. We quantified the distribution of tumor volume across body regions and used unsupervised cluster analysis to group patients based on tumor distribution. We correlated the presence and volume of internal tumors with disease-related and demographic factors. RESULTS: WBMRI identified 1286 tumors in 145/247 patients (59%). Schwannomatosis patients had the highest prevalence of tumors (P = 0.03), but NF1 patients had the highest median tumor volume (P = 0.02). Tumor volume was unevenly distributed across body regions with overrepresentation of the head/neck and pelvis. Risk factors for internal nerve sheath tumors included decreasing numbers of cafe-au-lait macules in NF1 patients (P = 0.003) and history of skeletal abnormalities in NF2 patients (P = 0.09). Risk factors for higher tumor volume included female gender (P = 0.05) and increasing subcutaneous neurofibromas (P = 0.03) in NF1 patients, absence of cutaneous schwannomas in NF2 patients (P = 0.06), and increasing age in schwannomatosis patients (p = 0.10). CONCLUSION: WBMRI provides a comprehensive phenotype of neurofibromatosis patients, identifies distinct anatomic subgroups, and provides the basis for investigating molecular biomarkers that correlate with unique disease manifestations.

Adiponectin, an adipokine secreted by adipocytes, exerts beneficial effects on glucose and lipid metabolism and has been found to improve insulin resistance by decreasing triglyceride content in muscle and liver in obese mice. Adiponectin is found in several isoforms and the high-molecular weight (HMW) form has been linked most strongly to the insulin-sensitizing effects. Fat content in skeletal muscle (intramyocellular lipids, IMCL) and liver (intrahepatic lipids, IHL) can be quantified noninvasively using proton magnetic resonance spectroscopy ((1)H-MRS). The purpose of our study was to assess the relationship between HMW adiponectin and measures of glucose homeostasis, IMCL and IHL, and to determine predictors of adiponectin levels. We studied 66 premenopausal women (mean BMI 31.0 ± 6.6 kg/m(2)) who underwent (1)H-MRS of calf muscles and liver for IMCL and IHL, computed tomography (CT) of the abdomen for abdominal fat depots, dual-energy X-ray absorptiometry (DXA) for fat and lean mass assessments, HMW and total adiponectin, fasting lipid profile and an oral glucose tolerance test (homeostasis model assessment of insulin resistance (HOMA(IR)), glucose and insulin area under the curve). There were strong inverse associations between HMW adiponectin and measures of insulin resistance, IMCL and IHL, independent of visceral adipose tissue (VAT) and total body fat. IHL was the strongest predictor of adiponectin and adiponectin was a predictor of HOMA(IR). Our study showed that in premenopausal obese women HMW adiponectin is inversely associated with IMCL and IHL content. This suggests that adiponectin exerts positive effects on insulin sensitivity in obesity by decreasing intracellular triglyceride content in skeletal muscle and liver; it is also possible that our results reflect effects of insulin on adiponectin.

Recent studies have demonstrated an important physiologic link between bone and fat. Bone and fat cells arise from the same mesenchymal precursor cell within bone marrow, capable of differentiation into adipocytes or osteoblasts. Increased BMI appears to protect against osteoporosis. However, recent studies have suggested detrimental effects of visceral fat on bone health. Increased visceral fat may also be associated with decreased growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels which are important for maintenance of bone homeostasis. The purpose of our study was to assess the relationship between vertebral bone marrow fat and trabecular bone mineral density (BMD), abdominal fat depots, GH and IGF-1 in premenopausal women with obesity. We studied 47 premenopausal women of various BMI (range: 18-41 kg/m², mean 30 ± 7 kg/m²) who underwent vertebral bone marrow fat measurement with proton magnetic resonance spectroscopy (1H-MRS), body composition, and trabecular BMD measurement with computed tomography (CT), and GH and IGF-1 levels. Women with high visceral fat had higher bone marrow fat than women with low visceral fat. There was a positive correlation between bone marrow fat and visceral fat, independent of BMD. There was an inverse association between vertebral bone marrow fat and trabecular BMD. Vertebral bone marrow fat was also inversely associated with IGF-1, independent of visceral fat. Our study showed that vertebral bone marrow fat is positively associated with visceral fat and inversely associated with IGF-1 and BMD. This suggests that the detrimental effect of visceral fat on bone health may be mediated in part by IGF-1 as an important regulator of the fat and bone lineage.